Herpes infections represent one of the most common viral infections that exist in the world. These viruses can be subclinical or as in the case of Kaposi's Sarcoma Associated Herpesvirus (KSHV) they can lead to dangerous diseases such as cancer. KSHV is well known in AIDS patients to cause Kaposi's Sarcoma (KS) and several other lymphoproliferative diseases. These viruses setup infection in oral cavities and can be transmitted orally. The overall goal of this application is to define the interactions between KSHV and the innate immune response the virus elicits in infected cells in the oral cavity. We will focu on the innate immune response to KSHV infection, especially the Type I Interferon response. Type I Interferon is well known to be the body's natural anti-viral system and almost all viruses that cause infection in humans have devolved ways to block or use this system to enhance their replication in the host. The goal of this project is to lead to the development of novel, innate immune based therapeutics harnessing the power of the innate immune system to directly stop KSHV replication. We were the first group to determine how the innate immune system can recognize herpesviruses (including KSHV) and have also defined the signaling mechanisms that induce interferon (from the host side) and block interferon (from the virus side). This application is setup to determine how these systems interact together to lead to infection and disease. Long term work from this R03 grant will setup preliminary data to apply for a larger R01 grant that will explore how these mechanisms can be modulated to fight KSHV infection and associated diseases.